chr11-64804769-C-A

Variant names:

• chr11-64804769-C-A
• rs990566024
• NM_001370259.2:c.1398G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001370259.2(MEN1):​c.1398G>T​(p.Glu466Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,444,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E466G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.176
• Publications: 0 publications found

Genes affected

MEN1 (HGNC:7010): (menin 1) This gene encodes menin, a tumor suppressor associated with a syndrome known as multiple endocrine neoplasia type 1. Menin is a scaffold protein that functions in histone modification and epigenetic gene regulation. It is thought to regulate several pathways and processes by altering chromatin structure through the modification of histones. [provided by RefSeq, May 2019]

MEN1 Gene-Disease associations (from GenCC):

• multiple endocrine neoplasia type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Ambry Genetics
• familial isolated hyperparathyroidism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pituitary gigantism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the MEN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 113 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Trascript score misZ: 4.1921 (above the threshold of 3.09). GenCC associations: The gene is linked to multiple endocrine neoplasia type 1, hereditary pheochromocytoma-paraganglioma, pituitary gigantism, familial isolated hyperparathyroidism.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21740553).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.1398G>T	p.Glu466Asp	missense_variant	Exon 10 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.1398G>T	p.Glu466Asp	missense_variant	Exon 10 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000445 AC: 1 AN: 224944 AF XY: 0.00000799

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000980

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1444528 Hom.: 0 Cov.: 43 AF XY: 0.00000139 AC XY: 1 AN XY: 718832

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5474

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110850

Other (OTH) AF: 0.00 AC: 0 AN: 60108

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 1 Uncertain:2

Nov 23, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 466 of the MEN1 protein (p.Glu466Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of MEN1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 457294). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MEN1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Mar 02, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Uncertain:1

May 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E466D variant (also known as c.1398G>T), located in coding exon 9 of the MEN1 gene, results from a G to T substitution at nucleotide position 1398. The glutamic acid at codon 466 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and aspartic acid is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.;.;.;.;D;D;D;D
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.84	T;T;.;.;T;.;.;T;.
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	-0.11	.;.;.;.;.;N;N;N;N
PhyloP100		-0.18
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.48	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.59	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.61	T;T;T;T;T;T;T;T;T
Polyphen		0.0010	.;B;B;B;B;B;B;B;B
Vest4		0.10
MutPred		0.45		.;.;.;.;.;Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);
MVP		0.51
MPC		0.95
ClinPred		0.19	T
GERP RS		1.6
Varity_R		0.064
gMVP		0.69
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs990566024; hg19: chr11-64572241;